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I’ve been going into podcast overload lately, mainly because of this boing boing post. Wanted to alert you all to the high quality and interesting sound engineering of Radio Lab if you didn’t know about it already. I’ve jammed the Memory, Placebo, and Stress episodes so far and was pleased overall with the level of informativeness, though I always prefer for brain regions to have names rather than descriptions. The Memory episode features Joe Ledoux and Karim Nader discussing the reconsolidation revival that occurred a few years ago.

In other news, The Sound of Young America has cool guests and The Rub has been doing a History of Hip Hop series that is worth your time.

• Category: Science 
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Did you know that neurons have resonant properties? I didn’t know that until I read this paper from the Johnston lab down in Austin, TX. Usually I think of synaptic transmission in terms of a single action potential or other event that releases neurotransmitter, so I don’t end up in the frequency domain. But, of course, the pattern of release is just as important as the magnitude. Neurons can fire in rhythmic patterns that have additive effects downstream because of the principle of temporal summation. Neurons are continuously deciding whether to fire or not. In a simple view, they do this by summing the ‘aye’ and ‘nay’ votes across all inputs. Aye votes move the voltage potential across the neuronal membrane in a positive direction by allowing positive ions to flow into the cell. There is a time window in which an input can cast its vote and still be counted based on how long it takes the receiver neuron to respond to inputs and how long it takes to return to a clean slate after responding. This allows the same input to vote several times if it does so at just the right frequency. If it tries to go too fast it will run up against the membrane capacitance. You see, the membrane potential isn’t exactly a count of the number of positive and negative charges inside and outside the cell. Rather, the ions have to be lined up right next to the membrane producing a capacitive current for the period of time it takes to push positive charges off the outside of the cell and line other ions up on the inside. People familiar with basic principles of electrical circuits know that charging a capacitor adds a time dimension. So if an input votes too fast, say, at a frequency of more that 10 to 20 Hz (I’m not sure of the exact number) the effect will be attenuated as the receiver simply can’t add that fast.

On the other hand, firing too slow simply won’t do either. Neurons have components that react to any change in membrane potential and push back toward baseline. Of particular interest is the H-conductance. The H-conductance is an ion channel in the membrane that allows positive ions to flow into the neuron (as long as the membrane potential is more negative than -30ish mV). Curses. I didn’t want to, but I think I have to explain reversal vs. activation potential. Reversal: Ions want to flow to places where there is a lower concentration. They want room to spread out and have a nice big yard with a swingset for the kids and all that, but they also want to get away from other ions with the same type of charge. So if there were a bunch of K+ ions sitting inside a cell and only a few outside and a channel opened up they would want to go out, but if there are already a bunch of Na+ ions outside then they might think twice because there is too much positivity out there already. In other words, potential and concentration gradients are taken into consideration. SInce there is a lot of Na+ outside the cell, it wants to flow into the cell and drive the potential up. There is a lot of K+ inside a neuron, so it wants to flow out of the cell and drive the potential down. If you open a channel that allows both ions through they will arrive at a consensus (equilibrium, reversal) potential that accommodates everyone’s needs. The H-conductance does just that and arrives at around -30 mV. If the membrane was at -30 mV, no net ion flow would occur. If it strays, the driving forces will push back towards -30. Normally, due to other considerations, a neuron sits near -55 to -60 mV, so activating the H-conductance will push the neuron toward a more positive potential. Now Activation: Ion channels respond to changes in membrane potential by opening and closing. The H-conductance is closed at positive potentials and becomes activated when the potential moves more negative than about -60 mV. This has the effect of opposing hyperpolarization, the increased difference in voltage across the membrane, because when the membrane tries to move more negative the channel opens and pushes positive. Since the activation potential for H-conductance is near the resting membrane potential, it can also oppose depolarization by shutting portion of channels and reducing the push towards positive. Finally, channel activation and inactivation takes time. It takes more time than charging the membrane capacitance. If an input wants to make a difference, it has to get its votes in before the H-conductance comes into play and brings everybody back to baseline. In this way, the H-conductance acts as a high-pass filter, only allowing speedy inputs to have a say.

Now we have a window of input frequencies that can really strongly affect the cell. If they are too fast, they are filtered out by the membrane capacitance. If they are too slow, they are filtered out by the H-conductance. Really the H-conductance is just one type of conductance that might do the job. Any conductance that is activated near resting membrane potential and opposes change would work fine. You can measure how this plays out in a real cell using something called an impedance amplitude profile (ZAP). You measure the voltage change in a neuron as you inject current at different frequencies but constant amplitude. In practice, this is done really quickly as a sweep across the frequencies. The result is a peak voltage change that corresponds to the resonant frequency of the cell. Like so:

Narayanan and Johnston already knew that you could measure resonant properties of neurons. What we didn’t know was that these properties varied in space and time. They measured resonance in CA1 pyramidal neurons. These are the major excitatory cells in an important region of the hippocampus, a brain structure responsible for memory encoding and spatial navigation. CA1 neurons are some of the best characterized neurons available because the CA1 region is highly accesible for in vivo recording and easily delineated for slice electrophysiology, and much is known about its specific inputs and outputs. Imagine an Egyptian pyramid. Now imagine a giant tree growing up through the center of it to about 10 times its height. That is what a pyramidal neuron looks like. The roots of the tree are basilar dendrites and the branches are apical dendrites. Dendrites are specialized structures for receiving input. One giant root will run out of the bottom of the pyramid and send output to some downstream cell. This is the axon. One of the first things that Narayanan and Johnston showed was that the resonant frequency of a CA1 neuron varies along the apical extent of the dendritic tree. The frequency increases as you get further toward the top of the tree, from 3 Hz to 8 Hz at the top. This correlates with the quantity of the channels responsible for H-conductance which also increases toward the tippy-tops of the tree. Input into CA1 neurons is spatially organized such that the entorhinal cortex inputs at the very tip of the apical extent while the CA3 region of the hippocampus inputs at sites more proximal to the cell body. One hypothesis that the authors put forward is that the resonant properties may be tuned to the specific types of inputs. Unfortunately, I can’t tell you whether entorhinal neurons fire at 8 Hz vs 3 Hz. I think this is an interesting avenue, but I wonder why you would need to filter the inputs by frequency if you already have them filtered by space. I suppose if the entorhinal cortex naturally fires around 8 Hz and you want the maximal downstream effect then its not so much a matter of filtering out bad frequencies as enhancing the good ones.

The most interesting thing to me though was that certain excitation patterns could alter the resonant frequency. If, by direct stimulation, they caused the neuron to fire in bursts separated by about 100 ms, they could later observe a upward shift in the resonant frequency. Th
ey used several stimulation protocols. Of highest interest was the effect of inducing LTP. LTP (Long-Term Potentiation) is a cellular model for learning in memory. It involves the seleective strengthening of synapses between two coincidentally active neurons. There are various LTP inducing stimulation protocols. The one these folks used requires stimulating axons headed for the apical dendrites of the CA1 neuron while depolarizing the CA1 neuron’s cell body to cause it to fire. Thus input activity is paired with downstream firing and that particular input is strengthened. Coincident firing is detected by a special receptor (the NMDA receptor) that is activated only when post-synaptic (dendritic, receiving end) membrane depolarization is paired with neurotransmitter release (from an axon of another neuron). After LTP induction, that input now has a bigger say in the overall activation election of the downstream neuron. The analogy between LTP and learning has been argued for decades now and some good evidence exists that this is a legitimate model. Early attempts to show this involved blocking the NMDA receptor in LTP and in learning and showing that both were impaired. Here is the key interesting thing for me about Narayanan and Johnston’s paper. Blocking the NMDA receptor not only blocked LTP, but also blocked a global, non-input specific, upward shift in the resonant frequency of CA1 neurons. Now we have two physiological phenomena that you are manipulating when you inject an animal with an NMDA receptor antagonist. Is learning disrupted because of failed LTP or failed resonance shifts?

Why would a resonance shift matter? Here’s one reason. Neurons don’t work alone. Thousands of neurons have to send input to one downstream neuron to get any reaction. They need to do this in a temporally coordinated fashion. One of the best methods for temporal coordination is oscillatory firing. Watch a tug of war sometime and note the effectiveness of “1,2,3 PULL!” compared to everybody struggling on their own time. This coordinated group of neurons is referred to as an ensemble. If members of the ensemble are connected to each other, they can settle on a frequency of oscillation that best excites everyone at once. If anyone gets out of line and starts going faster or slower, the big PULL will drag them back in, unless they are so far out that they simply can’t get down with a certain tempo. If a CA1 neurons is part of some larger ensemble that really loves to fire at 3 Hz and then its resonant frequency jumps up to 5 Hz, it will be that much less responsive to its former buddies. Instead, some other more enticing fast-paced ensemble might recruit that dude into their little 5 Hz cult. The implication is that NMDA receptor-dependent learning could be caused by changes in ensemble size and strength rather than or in addition to strengthening or weakening of specific synapses. A good place to begin on testing this implication would be to record from CA1 neurons in live, behaving animals (this is routine) during a learning task and note whether their preferential firing pattern shifts in frequency and whether this is coordinated across multiple neurons.

The H-conductance has more effects than just determining the resonant frequency. The Narayanan and Johnston paper was published alongside an article describing their effect on active properties of dendrites (dendritic calcium spikes) and third paper featuring the H-conductance prominently.

• Category: Science • Tags: Memory 
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The first genome-wide association study on human episodic memory back in 2006 showed an association between the T allele of a gene called KIBRA and better performance on certain list-learning tasks. That study contained two replications in different populations, and the outcome was independently replicated in healthy, elderly folks. Next, another group showed an association between the T allele and very late-onset Alzheimer’s. There are some issues with interpreting this study that I certainly didn’t think of the first time I read it. Almeida et al. point out that this could be due to ‘survivorship bias’ wherein the C allele carriers that were gonna get AD got it a lot earlier and left the T allele folks to provide the ‘very late-onset’ crowd (or at least that’s how I interpret survivorship bias).

Two studies have come out in the past few months. One replicates the effect of the T allele on memory with a little smaller effect size than before. The second fails to find any effect at all. One experiment in this latter report was an exact replication of the 2006 memory study with a population of European origin (German vs. Swiss. That shouldn’t matter should it?).I don’t know how to explain the failure to replicate, but it is duly noted. Perhaps it really really matters how well you vet your cohort. For instance (from Almeida and co again):

We did not find evidence in support of our original hypothesis that CC carriers would be at greater risk of MCI (ed: Mild Cognitive Impairment) (although we did observe a trend in that direction), nor were we able to show any evidence of an effect of the gene on the memory scores of older people with MCI. These results suggest that the effect size of the T→C polymorphism decreases with increasing impairment of episodic memory, and that the KIBRA gene plays all but a limited role after scoresfall below a certain threshold, as is the case in MCI.

I don’t think there is any evidence that the cohort that failed to replicate had especially bad memory, but I’m not an expert in human memory assessment. A few more molecular details below:

Kibra had an especially good tie-in to memory because in yeast two-hybrid studies it binds to PKM zeta which is established as a key player in maintenance of several types of memory and synaptic plasticity in a completely separate literature. The molecular situation is foggy as well though. We don’t have any published assessment of the function or localization of endogenous Kibra protein in neurons. In fact, most of the molecular work has been done with an overexpressed GFP fusion protein. The group that discovered Kibra reports that it is a 125-kDa protein with specialized “WW” protein interaction domains at one end, while the group that reported the Kibra-memory association used a custom antibody to detect human Kibra protein and identified a 100-kDa truncated protein. One final issue is that the memory-SNP (and all SNPs in linkage disequilibrium) in human Kibra is intronic, which means we have no straightforward prediction as to how it might alter protein function. Papassotiropoulos et al.(2006) could not find a difference in the total amount of Kibra protein in human brain tissue with different alleles. Either we have to predict that the SNP produces an expression change that they couldn’t detect or that the SNP alters splicing such that the protein sequence changes but the size doesn’t.

• Category: Science • Tags: Memory 
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The Center for Strategic and International Studies has a report out (available here) entitled, “Synthetic Genomics: Options for Governance.” I haven’t read the whole thing, but it looks to be a consideration of the options for minimizing risks associated with widespread use of this technology. They are concerned first and foremost with malicious uses followed by lab safety and environmental safety. Take a look if policy is your bag. No recommendations, just laying options on the table.

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Do two points make a line?

Better Memory and Neural Efficiency in Young Apolipoprotein E epsilon4 Carriers

The apolipoprotein E (APOE) epsilon4 allele is the major genetic risk factor for Alzheimer’s disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE epsilon4 with better episodic memory compared with APOE epsilon2 and epsilon3 in 340 young, healthy persons.

The T allele of KIBRA was found associated with better memory in a genome-wide association study last year. And now this:

Age-dependent association of KIBRA genetic variation and Alzheimer’s disease risk.

An association between memory performance in healthy young, middle aged an elderly subjects and variability in the KIBRA gene (rs17070145) has been recently described. We analyzed this polymorphism in 391 sporadic Alzheimer’s disease (AD) patients and 428 cognitively normal control subjects. The current study reveals that KIBRA (rs17070145) T allele (CT and TT genotypes) is associated with an increased risk (OR 2.89; p=0.03) for very-late-onset (after the age of 86 years) AD.

I haven’t done an exhaustive search, but there appears to be about four more human memory-associated genes. I wonder if they’ll form a pattern. By the way, it looks like these cats Papassotiropoulos and de Quervain have the memory genome-wide association game on lock. Can someone with the right kind of knowledge take a look and see if they are doing things in a robust way? I don’t really know what alternative hypotheses you have to get rid of before you can claim an association.

• Category: Science • Tags: Memory 
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Pardon the interruption, but if anyone has successfully used Parallels with a Windows XP partition in Boot Camp that is FAT 32 configured would you please drop a line (clicking the name “amnestic” above will result in a pop-up window with a contact box)? I have been combing through the knowledge bases, blog entries, and forums for a couple days and I am still stuck with “Unable to open disk image Boot Camp!” Frustration mounts.

• Category: Science 
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One of my favorite recent ideas wondering through the literature is that of an RNA regulon or post-transcriptional operon. Operons in prokaryotes are groups of genes whose protein products all function in the same biochemical pathway. The genes are coordinated by sticking them all next to each other and transcribing all when you transcribe one. The post-transcriptional operon idea is that RNA motifs allow proteins in the same biochemical pathway to be regulated at the translation step instead. If several proteins were needed, for instance, to build some new architecture sticking off a cell at a specific location far from the nucleus, it wouldn’t do to have to coordinate them way back there. Instead, you just throw in an RNA motif, say AUUUA. Then produce an RNA binding protein that is specific for that motif. Now traffic that protein to the location of interest. All of the RNAs will be localized to the right spot.

Of course, localizaton is just one way this could work. Any process better controlled faster or farther away from the nucleus could use an RNA regulon. One notable case is that of the Pumilio family (Puf) RNA-binding proteins in yeast. Melissa J. Moore explains it here:

… each Puf protein exhibited a highly skewed distribution of bound mRNAs: Puf1p and Puf2p bound mostly mRNAs encoding membrane-associated proteins, Puf3p almost exclusively targeted messages for nuclear-encoded mitochondrial proteins, and Puf4p and Puf5p associated primarily with transcripts encoding proteins bound for the nucleus. In several cases, a majority of the subunits comprising a particular multiprotein machine, such as the mitochondrial ribosome and a number of nuclear chromatin modification complexes, were encoded by mRNAs “tagged” by a single Puf protein. Together with earlier data (12), these new results (16) strongly support the idea that the expression of proteins with common functional themes or subcellular distributions is coordinated by large-scale regulatory networks operating at the mRNP level.

Many other examples can be found in this review by Jack Keene. I don’t think I’ve seen an example of this yet, but given the slight wobble in microRNA specificity, one could imagine a single microRNA regulating a whole set of genes. Also, most interesting for my neuro-tastes is the recent report from the Moore lab showing that the immediate-early gene implicated in neuronal homeostasis, Arc, may be part of a regulon defined by introns in the 3′UTR. The mechanism is just too clever but requires an explication on the “pioneer round” of translation. Basically the cell tricks itself into thinking it made a funky RNA and destroys it after one round of synthesis. The other RNAs regulated in this path in neurons must have opposing effects to Arc though because knocking down this negative regulation pathway led to increased excitability (increased Arc reduces neuronal excitability). This raises a more general question. The idea of RNA regulons is nice, but how much can you predict knowing that your gene of interest is part of one? RNAs associate with multiple complexes throughout their lifespan, and complexes gain and lose factors dynamically. Also, how promiscuous are RNA binding proteins for cellular processes? For instance, I originally became aware of the Hu proteins as positive regulators of the pre-synaptic calcium-buffering protein GAP-43, but it turns out that they also regulate proteins involved in immune function. Maybe I am just thinking at too high a level of cellular organization. Perhaps all of those proteins respond to calcium in some way. At any rate, I’m expecting that RNA regulons will be increasingly important in understanding the translational regulation that must take place in dendrites to produce persistent memories. Looking forward to more on that in the next year or so.

• Category: Science • Tags: Translation 
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AMPA receptors are the major receptors for excitatory neurotransmission. There is a firm basis for the hypothesis that synaptic plasticity and thus memory is based on the increase or decrease in the number of AMPA receptors in specific synapses. AMPA receptors are actually ligand-activated ion channels made up of subunits. Sodium passing through the AMPA channel depolarizes the membrane potential of the receiving neuron and pushes the cell toward firing. Calcium can also pass through AMPA channels, but there is one subunit, the GluR2 subunit, that can block calcium. AMPA receptors lacking GluR2 are relatively rare, so most AMPA receptors can’t pass calcium.

Calcium has implications beyond membrane potential changes because calcium acts as a signaling molecule activating enzymes downstream. Plant et al published a report last year showing that GluR2-lacking AMPA receptors are incorporated into synapses for about 25 minutes after induction of plasticity at a synapse, after which they are replaced by GluR2-containing AMPA receptors. They were able to perform these experiments by checking the sensitivity of plasticity to a drug that should only affect GluR2-lacking AMPA receptors. This is an interesting idea because it allows for an increase in calcium signaling at specific synapses that outlasts the inducing event. This calcium signaling could serve as a mark to show the slower synapse-building machinery to find the favored synapses and get to work.

However, all is not well because Adesnik and Nicoll published pretty much the opposite result in April. I mean both labs used phillanthotoxin, the special GluR2 drug, and one got an effect and one didn’t. I don’t know why, but controversy is so exciting, right? John Isaac wrote a response to the Adesnik and Nicoll paper defending the Plant et al findings, but it doesn’t really offer a concrete explanation for the differences. Anyone who can explain it to me gets a free hug if I ever see you.

Now, even more recently, Gray et al (TJ O’Dell’s lab) seconded Adesnik and Nicoll’s motion damaging the Plant/Isaac thesis. Very similar to the previous two publications but using a different drug and a different waterbath temperature, O’Dell and colleagues could find no indication that GluR2-lacking receptors were necessary for long-term plasticity. When two independent laboratories shoot down a high-profile finding, no matter how theoretically appealing, it is probably time to let it go. It is a shame that the null finding and its replication weren’t published in quite as high-tier journals as the first.

Here are two recent reviews on AMPA receptors and GluR2:
Regulatory mechanisms of AMPA receptors in synaptic plasticity
The Role of the GluR2 Subunit in AMPA Receptor Function and Synaptic Plasticity
Keep an eye on the publication dates. The second review here addresses the Adesnik and Nicoll finding, but neither of them address Gray et al.

• Category: Science 
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Rapid Erasure of Long-Term Memory Associations in the Cortex by an Inhibitor of PKM{zeta}
Reut Shema, Todd Charlton Sacktor, Yadin Dudai

Little is known about the neuronal mechanisms that subserve long-term memory persistence in the brain. The components of the remodeled synaptic machinery, and how they sustain the new synaptic or cellwide configuration over time, are yet to be elucidated. In the rat cortex, long-term associative memories vanished rapidly after local application of an inhibitor of the protein kinase C isoform, protein kinase M zeta (PKM{zeta}). The effect was observed for at least several weeks after encoding and may be irreversible. In the neocortex, which is assumed to be the repository of multiple types of long-term memory, persistence of memory is thus dependent on ongoing activity of a protein kinase long after that memory is considered to have consolidated into a long-term stable form.

The authors used conditioned taste aversion (you may be familiar with this learning paradigm if you’ve ever made yourself sick off tequila). Injection of a peptide inhibitor of this enzyme (PKM zeta) completely removed the aversive association. This isn’t a paper about how to erase memories for any clinical application because, for instance, injecting the drug erases multiple olfactory associations (i.e. we don’t have a clue how to achieve specificity). It is a paper about how memory works, and it is pretty remarkable that a simple mechanism like persistent kinase activation may be central to this neural function.

• Category: Science • Tags: Memory 
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I did a poor job asking pubmed for the paper Razib mentioned earlier, but this surely does look interesting:

Brain pathology in pedophilic offenders: evidence of volume reduction in the right amygdala and related diencephalic structures.
Kolja Schiltz, Joachim Witzel, Georg Northoff, Kathrin Zierhut, Udo Gubka, Hermann Fellmann, Jörn Kaufmann, Claus Tempelmann, Christine Wiebking, Bernhard Bogerts

CONTEXT: Pedophilic crime causes considerable public concern, but no causative factor of pedophilia has yet been pinpointed. In the past, etiological theories postulated a major impact of the environment, but recent studies increasingly emphasize the role of neurobiological factors, as well. However, the role of alterations in brain structures that are crucial in the development of sexual behavior has not yet been systematically studied in pedophilic subjects. OBJECTIVE: To examine whether pedophilic perpetrators show structural neuronal deficits in brain regions that are critical for sexual behavior and how these deficits relate to criminological characteristics. DESIGN: Amygdalar volume and gray matter of related structures that are critical for sexual development were compared in 15 nonviolent male pedophilic perpetrators (forensic inpatients) and 15 controls using complementary morphometric analyses (voxel-based morphometry and volumetry). Psychosocial adjustment and sexual offenses were also assessed. RESULTS: Pedophilic perpetrators showed a significant decrease of right amygdalar volume, compared with healthy controls (P = .001). We observed reduced gray matter in the right amygdala, hypothalamus (bilaterally), septal regions, substantia innominata, and bed nucleus of the striae terminalis. In 8 of the 15 perpetrators, enlargement of the anterior temporal horn of the right lateral ventricle that adjoins the amygdala could be recognized by routine qualitative clinical assessment. Smaller right amygdalar volumes were correlated with the propensity to commit uniform pedophilic sexual offenses exclusively (P = .006) but not with age (P = .89). CONCLUSIONS: Pedophilic perpetrators show structural impairments of brain regions critical for sexual development. These impairments are not related to age, and their extent predicts how focused the scope of sexual offenses is on uniform pedophilic activity. Subtle defects of the right amygdala and closely related structures might be implicated in the pathogenesis of pedophilia and might possibly reflect developmental disturbances or environmental insults at critical periods

• Category: Science • Tags: Amygdala 
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Recently purchased a video iPod. I am the nerd sitting outside the coffeeshop groking brain network dynamics on my tiny screen. At least my case is stylish.

Here is a trove on that subject:
Conference on Brain Network Dynamics, 1/26/2007

That conference was in part a tribute to Walter Freeman. Here is more from him:
Poetry of Brains

Digging around more you can find several videos from the Redwood Center for Theoretical Neuroscience. For instance, Micro-circuits of Episodic Memory: Structure Matches Function in the Hippocampal System, and a debate entitled “Waves or words in cortex?” featuring Professor Freeman again.

On the mathy tip, you can download .mov’s on some pretty interesting topics from the Mathematical Sciences Research Institute. If someone can point me to a converter so I can carry them around with me I would be muy grateful. I’m more interested in the ones that seem to have some relation to biology such as Frances Tong on Normalization of Western Blots.

Speaking of .movs to convert. I found an extensive discussion by Mark Ptashne on his book, A Genetic Switch. Presumably this coincided with the release of the new edition: A Genetic Switch, Lecture Series.

• Category: Science 
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Kosik and colleagues used laser capture microdissection to get RNA populations from dendrites or cell bodies of cultured rat neurons. They optimized their technique so that mRNAs known to be enriched in dendrites, such as CaMKII and MAP2, showed about equal levels from soma and dendrite. They then performed multiplex PCR for several mRNAs and 187 miRNAs. The distribution of mRNAs and miRNAs is similar with a large somatic population and a gradient going out into the dendrites. Some small proportion of miRNAs have a little bit of dendritic enrichment. One point the authors are trying to get across is that there is no such thing as a ‘dendritic RNA’ because even the mRNAs and miRNAs that show some dendritic localization usually show just as much in the cell body.

Two nice things are that this paper validates a couple miRNA target prediction programs (Pictar and Targetscan) and that they provide a quantitative view of the miRNA copy number per cell. Both of these prediction programs suggested that miR-26a would target MAP2. This is convenient since both showed a somatodendritic distribution, meaning they hang out together even out at the farthest dendritic reaches. Inhibition of miR-26a with a synthetic oligonucleotide resulted in increases in MAP2 protein expresion, as one would expect from the classic miRNA-target relationship. As far as I am aware this brings the total of known dendrtici miRNA target pairs up to three, the other two being mir-268 and CaMKII (in drosophila) and miR-134 and LIM-Kinase. Quantification was achieved using PCR with known copy number standards. They knew how many cell bodies they captured, so they could get a copy number per cell estimate (probably a minor undershoot since even if they are awesome they probably couldn’t save allllll the RNA from degradation). Anyway, they found… well I’ll let them explain it:

rno-miR-124a is among the most abundant miRNAs in neurons and fell in the range of 10^4 copies per neuronal cell body. Despite its abundance, rno-miR-124a is enriched in cell bodies. rno-miR-26a and rno-miR-16 are less abundant miRNAs and fell in the range of 10^3 copies per neuronal cell body (Table 6). Because (delta)Ct of 2.61 +/- 0.39 describes the distribution of most miRNAs between the cell body and neurite, the number of copies of many miRNAs distributed along this gradient may be as low as in the hundreds of copies in the dendritic compartment. Even a one-order-of-magnitude error in this number is far below the number of synapses on the dendritic tree, and, therefore, the copy numbers of many miRNAs are likely to fall below one per synapse.

Delta Ct refers to the number of PCR cycles (i.e. doublings) it takes for the dendritic levels to reach the somatic levels. For instance, a delta Ct of 2.61 means that there are 2^2.61 (~6.1) times more somatic copies of the miRNA than there are dendritic copies.

I was particularly intrigued by this last sentence even though I have no idea what it means:

Stochasticity derived from the effects of miRNAs will contribute to the activation barrier for coherent responses, to the utilization of information provided by translational bursting, and to the flexibility needed by dendrites to sample alternative states (Kaern et al. 2005).

Guess I’ll have to read Kaern et al. real quick.

• Category: Science 
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I picked up a copy of Cerebrum 2007, a collection of essays related to neuroscience published by Dana Press. There were a couple good articles on stroke and pain (arguing that cancer patients have little danger of addiction even using infamous opioids like morphine), but I was disappointed by Henry Greely’s scaaarrry article about the potential negative uses of neuroscience discoveries. He catalogs past misuses of scientific authority, perhaps the most egregious of which was the widespread use of lobotomy. But what to make of this:

Before eugenics disappeared in America after World War II, about 60,000 men and women were surgically sterilized by court order, for conditions such as feeblemindedness, alcoholism, insanity, epilepsy, and criminality, which have little or no genetic basis.

Alcoholism? Really? Somebody better tell the NIAAA quick.

In response to the overwhelming evidence from twin, family, and adoption studies for a major genetic influence on vulnerability to alcoholism, NIAAA has funded the Collaborative Studies on Genetics of Alcoholism (COGA) since 1989, with the goal of identifying the specific genes underlying this vulnerability.

When it comes time to argue about whether fMRI lie detection schemes should make their way into court, let’s hope we can get our facts straight at least. As to the actual ethical questions raised, as in coerced fMRI or drug treatments I find my utilitarian standbys running up against my empathy. I suppose if you are doing nothing criminal and have no expectations of running up against the government you should have no concern about efficacious lie detection. On the other hand, I already think we have unjust laws on the books.

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The Henry Stewart free ‘talk of the month’ in on vascular tissue engineering.

Talk Summary

Tissue engineering approaches – Different cell sources for a blood vessel substitute – Circulating endothelial progenitor cells: their characteristics, their use in a blood cell substitute and recruitment from the host circulating blood – Differentiation from ES into endothelial cells in vitro and their endothelial-like characterization – The use of different types of scaffolds – in vivo and in vitro remodeling – Engineering immune acceptance – Clinical applications: EC-seeded ePTFE grafts for peripheral applications and cell-seeded polymer scaffold grafts for pulmonary artery/Fontan procedure.

Cell has a new podcast.

June Podcast

In our third podcast appearing online on 14th June 2007, Dr Emilie Marcus talks to Dr Jonathan Weissman about exciting new technologies that are changing the research enterprise and we hear from Dr John Kuriyan about how kinases keep themselves switched off until they are needed. We also learn about some of the exciting research published in Cell in the last few months, including a study by Dr Wolf-Dieter Schubert that shows how to coax a human pathogen to invade a mouse.

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There is a rather salty piece of correspondence in the new Nature Neuroscience from one Maureen Condic regarding Nature’s editorial position on the likelihood of development of ES cell-based therapies anytime soon. Apparently, Condic has a skeptical take on the issue and Nature had some disparaging words.

The issues of immune rejection, tumor formation and hESC differentiation raised in my article are not distortions or mere polemic; they are matters of scientific fact. These same concerns have been raised in the scientific literature and voiced by leading scientists in the stem cell field. James Thomson cautioned that “major roadblocks” must be overcome before hESC-derivatives could be safely transplanted into patients, and concluded that surmounting these roadblocks will be “likely to take a long time”. Similarly, Robert Lanza noted that immune rejection is a significant problem, and warned that creating hESC lines to match most patients “could require millions of discarded embryos from IVF clinics”. Although the editors dismiss as “tenuous” the connection between therapeutic use of hESCs and the genetic/epigenetic abnormalities introduced during cloning, this same concern was raised by Jose Cibelli’s recent article in Science.

I think it is important to hear about these obstacles and be realistic about what ES cells could provide. There are other uses of ES cells besides implantation type therapy, of course. For instance, they aid the understanding of basic cell differentiation and cell cycle regulation, topics that are important in cancer research.

The problem for me is that I find the ‘moral’ objections ridiculous. So if ES cells have any therapeutic or just plain scientific potential at all, then I’m all for it. Am I living in naive bliss thinking that most average people wouldn’t give a damn after they really understood what a blastocyst is? Right now, I’m thinking that this is one of a few scientific areas where you could educate the public and actually impact policy in a positive way.

There appears to be a semi-lively debate underway over at the Nature Neuro news blog: Action Potential.

• Category: Science • Tags: Politics 
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RNA interference is a process by which small (20-22 nt) RNAs bind to a fully or partially complementary messenger RNA and reduce the amount of protein product from that mRNA. The general rule is that if the match is perfect (full complementarity) then the target mRNA is cut into two pieces and destroyed forthwith. If the match is imperfect such that there are bulges in the double stranded RNA that forms between the interfering RNA and the target, then the target is sequestered to a newly discovered cellular entity called a Processing Body (P Bodies, PBs). There are enzymes in PBs capable of degrading mRNAs, but sometimes the mRNAs can be released and become translationally competent again.

New research from Kiriakidou et al in Cell provides a mechanism for this translational repression sans degradation. The effects of small interfering RNAs (siRNAs) are mediated by the Argonaute family of proteins (Ago1, Ago2, etc). This family can be subdivided depending on the proteins’ ability to cleave RNA and thus carry out the “perfect-match” type of translational repression, but even non-cleaving Agos can do the sequestration route for repression. The latest news is that this can be achieved by blocking interactions between the cap-binding translation initiation factor eIF4E and the 5′ cap of mRNAs.

Let me unpack. For efficient initiation of protein synthesis from an mRNA, several proteins must assemble into complexes centered around the mRNA. There are several proteins that bind near the other end of the mRNA where there is a cap. A cap is a modified guanine nucleotide flipped around backward and stuck on the head-end of the mRNA early in its life. One protein in particular, eIF4E recognizes the cap structure and binds to it, recruiting other initiation factors and eventually the small ribosomal subunit. This is an important and highly regulated step in protein synthesis. For instance, there is a family of proteins (4E-BPs) whose sole function is to bind eIF4E and get in the way of cap-binding. If they become highly phosphorylated because of this signaling pathway or that, they let go and translation proceeds. Ago proteins can do the same thing, but on the cap side and without the phosphorylation business.

They showed the effect by first purifying an Ago protein with and without important amino acids for cap-interaction and testing for binding with caps immobilized on a column. Only Ago proteins with the two important (phenylalanine) amino acids could bind. Further assays in vivo showed that the mutant Agos couldn’t mediate translational repression.

There are a couple predictions to make based on these findings.

1) Organisms with Agos that lack this domain should be bad at this process.

This domain is not found in Ago proteins of plants, archaea, or fission yeast, in Drosophila AGO2 and in most members of the C. elegans Ago protein family, with the exception of ALG-1 and ALG-2. In addition, the MC domain is absent from proteins of the PIWI family.

I can’t recall if any of there is anything already contradictory in that list. I think there is definitely something weird about the way plants handle siRNAs, but the details escape me.

2) RNAs that are capable of cap-independent translation should not be regulated by this process. There is debate about the degree to which mRNAs can undergo cap-independent translation, but the field is moving along as though internal ribosomal entry sites are an important cellular tool, so these RNAs should escape translational repression via this process.

• Category: Science • Tags: Translation 
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I know this isn’t the Learn Japanese forum, but when I have time for playing around I’ve been enjoying this Final Fantasy / Zelda takeoff that helps you with katakana, hiragana, and some kanji. It is called Slime Forest. The slimes attack and yell characters at you to which you must respond appropriately. Save the princess!

• Category: Science 
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A recent paper issue of Cell came with an ad for the Calcium Signalling series from Henry Stewart Talks. These are apparently nicely produced lecture-format videos from experts reviewing diverse areas of biology. I’m not willing to shell out the $690 it would take to view the whole thing, but they have a free talk of the month: Calcium, Calmodulin, and Calcineurin by Stephen Bolsover that you might want to kick back with a glass of red and consume.

• Category: Science • Tags: Video Type 
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People who study glia are getting all excited about the ‘tripartite synapse’ where astrocytes that wrap around the synaptic cleft play an active role in controlling neurotransmission. Well TAKE THAT glia researchers!

Selective Stimulation of Astrocyte Calcium In Situ Does Not Affect Neuronal Excitatory Synaptic Activity

Todd A. Fiacco, Cendra Agulhon, Sarah R. Taves, Jeremy Petravicz, Kristen B. Casper, Xinzhong Dong, Ju Chen and Ken D. McCarthy


Astrocytes are considered the third component of the synapse, responding to neurotransmitter release from synaptic terminals and releasing gliotransmitters—including glutamate—in a Ca2+-dependent manner to affect neuronal synaptic activity. Many studies reporting astrocyte-driven neuronal activity have evoked astrocyte Ca2+ increases by application of endogenous ligands that directly activate neuronal receptors, making astrocyte contribution to neuronal effect(s) difficult to determine. We have made transgenic mice that express a Gq-coupled receptor only in astrocytes to evoke astrocyte Ca2+ increases using an agonist that does not bind endogenous receptors in brain. By recording from CA1 pyramidal cells in acute hippocampal slices from these mice, we demonstrate that widespread Ca2+ elevations in 80%–90% of stratum radiatum astrocytes do not increase neuronal Ca2+, produce neuronal slow inward currents, or affect excitatory synaptic activity. Our findings call into question the developing consensus that Ca2+-dependent glutamate release by astrocytes directly affects neuronal synaptic activity in situ.

I kid. I’m sure glia are more than support cells. They really are more active and reactive than people had given them credit for. Perhaps if they don’t directly affect fast neurotransmission they could modulate glutamate driven synaptic plasticity.

• Category: Science 
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Redefinition / turnin’ your play into a tragedy / exhibit level degree on the mic / passionately – Kweli

Nature has an Insight section up ostensibly about epigenetics starting with an article by Adrian Bird suggesting a re-definition. It’s free. I think the term is useful to the extent that you can predict something about a phenomenon or mechanism by knowing that it is ‘epigenetic’. Bird’s suggestion is to make the term less useful and more inclusive. The last section is labeled ‘Refining a definition’ when in fact he is doing just the opposite:

…there might be a place for a view of epigenetics that keeps the sense of the prevailing usages but avoids the constraints imposed by stringently requiring heritability. The following could be a unifying definition of epigenetic events: the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states. This definition is inclusive of chromosomal marks, because transient modifications associated with both DNA repair or cell-cycle phases and stable changes maintained across multiple cell generations qualify.

He wants to allow transience and yet use epigenetics to explain stable phenomena:

A growing idea is that functional states of neurons, which can be stable for many years, involve epigenetic phenomena, but these states will not be transmitted to daughter cells because almost all neurons never divide.

Without such epigenetic mechanisms, hard-won changes in genetic programming could be dissipated and lost;

With this refinement, epigenetics is everything and nothing. The only thing you can infer about an epigenetic event is that it doesn’t change the DNA sequence. Bird wants to claim that a unifying trait is that epigenetics is ‘responsive’ rather than ‘proactive’. I don’t understand. If you’re going to introduce new terms, why not choose to bring into to broader use the distinction between meiotically and mitotically heritable or force people to be specific about which chromatin modification they are referring to instead of saying ‘epigenetic modifications’? Responsive and proactive are more loosely defined concepts destined to muddy waters and lead away from insight.

• Category: Science • Tags: Epigenetics 
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